Project summary Recently, much attention has turned to the study of so-called oligomeric forms of the amyloid beta peptide (A)) as possible key mediators of dementia in Alzheimer's disease. We have chosen to exploit the propensity of Dutch A to form oligomers is order to create a transgenic mouse model of the biochemical pathology, neuropathology, and behavioral pathology of neuronally-derived A oligomers by overexpressing Dutch APP on the Thy1 promoter (Thy1-Dutch APPE693Q transgenic mouse line). In preliminary characterization of these Thy1-Dutch APPE693Q mice, we have observed aging-dependent cognitive decline and a number of quantifiable neuropathological changes. However, in our hands, Thy1-APPE693Q mice never develop parenchymal amyloid deposits of any sort during their lifespan; however, immunodetectable A oligomers accumulate, and these oligomers appear to be localized to the neuronal endosomal-lysosomal system. In order to generate A histopathology, we have crossed the Thy1- Dutch APPE693Q mice with familial Alzheimer's mutant presenilin lacking exon 9 (PS19). This pathogenic mutant form of PS1 elevates levels of A42, thereby causing plaques to form in bigenic mice (these mice are designated Thy1-Dutch APPE693Q x PS19 bigenics). However, while the mutant PS1 causes plaques to form, the appearance of amyloid plaques has no obvious effect on the time course or initial severity of cognitive decline. In summary, we observe: (1) accumulation of intraneuronal APP/A derivatives in single Dutch APP transgenic and bigenic PS/APP mice; and (2) accumulation of Dutch CAA. For this MERIT application, we propose to perform quantitative characterization of single Dutch APP transgenic and bigenic PS/APP mice, according to gender and at various ages over their lifespans, using (a) Assessment of behavioral performance in the Morris water maze and inhibitory avoidance models of spatial learning and memory; (b) Quantification of brain levels of APP, and CTFs, A40, A42, A oligomers, and synaptophysin; (c) Subcellular localization of APP-A-like immunoreactivity, including Dutch CAA; (d) Quantitative morphometry to determine integrity of hippocampal neuronal populations and to estimate intraneuronal A burden. The availability of lines of mice that are impaired by oligomers and never develop amyloid plaques would greatly facilitate the construction of in vivo efficacy screens in the search for anti- oligomer drugs for the treatment of Alzheimer's disease.